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Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor  (MC4R ); rs7566605 (insulin induced gene 2 ( INSIG2 ); rs9939609 and rs1121980 (fat mass and obesity associated  (FTO ) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r 2  = 0.2–0.6).  MC4R  rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in  MC4R  was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to  FTO  and  INSIG2  were not associated with any bone phenotypes in either cohort and  FTO  SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to  MC4R  is associated with quantitative ultrasound and risk of fracture.

Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women